Research over the past 20 years has produced an explosion of new information on the genetic changes that lead to malignancy. Yet this vast trove of knowledge has not led to a corresponding increase in new modalities for cancer therapy. This is, in part, attributable to the heterogeneity of cancer that guarantees that no single agent will be effective in all patients, and the difficulty of mining the complex genetic data to identify molecular targets and pathways that are most amenable to therapeutic intervention ("druggable"). To meet this challenge, funds are requested to create the Vanderbilt Molecular Target Discovery and Development Center (VMTDDC), an inter-institutional, multi-disciplinary collaboration between the Vanderbilt Institute of Chemical Biology (VICB) and the Vanderbilt Ingram Cancer Center (VICC). Building on the existing infrastructure and expertise of the VICB and VICC in chemical biology, drug discovery, and cancer research, the VMTDDC will establish a new paradigm for molecular target identification, validation, and development. Key to the innovative approach of the VMTDDC is the use of two-dimensional heteronuclear single quantum correlation (HSQC) NMR for molecular fragment- and structure-based drug design. This technology provides an efficient, high-throughput method to determine a potential target's druggability early in the process, thus maximizing efficiency in target selection. HSQC NMR also provides a rapid means to identify small molecules that bind to a potential target (molecular fragment leads), in addition to structural information that can be applied to rational lead optimization efforts. The VMTDDC will incorporate fragment-based drug design into an overall program of target identification and development. For the two year pilot project funding period, potential targets will be identified from aberrant signaling pathways identified through analysis of genomic data from triple negative breast cancer (TNBC), a particularly aggressive and drug resistant form of cancer. Potential targets will be validated by RNAi screening of 20 TNBC cell lines available in the VICC. Validated targets will be expressed and subjected to HSQC NMR evaluation for druggability, which also identifies molecular fragment leads. Druggable targets will be developed by a combination of fragment-based drug design and conventional high throughput screening of the VICB's 350,000 compound library, followed by structure-driven lead optimization. The ultimate goal is to identify novel, rationally selected molecular targets and to demonstrate their druggability using state-of-the-art chemical biology approaches. The VICB and VICC already possess much of the infrastructure, expertise, and leadership needed to develop the VMTDDC. The requested funding will provide the additional personnel, equipment, and material needed to allow an immediate shift of resources to a concentrated effort in the specific area of molecular target discovery and development, which will then be established as a long-term program at Vanderbilt. PUBLIC HEALTH RELEVANCE: Funds are requested to establish the Vanderbilt Molecular Target Discovery and Development Center (VMTDDC), a multi-disciplinary, inter-institutional collaboration with the aim of exploiting the wealth of cancer genomic data to identify and develop new treatment modalities for cancer. Key to the VMTDDC's innovative approach is the use of protein NMR for molecular fragment-based drug discovery, which efficiently identifies proteins that are amenable to small molecule drug development and provides critical information for lead identification and optimization. Through its combination of this ground-breaking technology with traditional drug discovery approaches, the VMTDDC will establish a new paradigm for cancer molecular target discovery and development.